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Home , Index case, Meherpur District

Epidemiol. Infect., Page 1 of 7. f Cambridge University Press 2010 doi:10.1017/S0950268810000695

Nipah outbreak with person-to-person in a district of , 2007

N. HOMAIRA 1,2*, M. RAHMAN 1,M.J.HOSSAIN2, J.H. EPSTEIN3,4, R. SULTANA2,M.S.U.KHAN2,G.PODDER2, K. NAHAR2,B.AHMED1, E. S. GURLEY 2,P.DASZAK4,W.I.LIPKIN5, P.E. ROLLIN6,J.A.COMER6, 6,7 2,6 T. G. KSIAZEK AND S. P. LUBY

1 Institute of , Control and Research (IEDCR) , Bangladesh 2 International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh 3 The Consortium for Conservation Medicine (CCM), New York, USA 4 Wildlife Trust, New York, NY USA 5 Center for and Immunity, Columbia University, New York, USA 6 Special Pathogens Branch, Division of Viral and Rickettsial Disease, National Centre for Infectious Disease, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA 7 Galveston National Laboratory, Department of Pathology, Galveston TX, USA

(Accepted 9 March 2010)

SUMMARY In February 2007 an outbreak of Nipah virus (NiV) encephalitis in of northwest Bangladesh affected seven people, three of whom died. All subsequent cases developed illness 7–14 days after close physical contact with the index case while he was ill. Cases were more likely than controls to have been in the same room (100% vs.9.5%, OR undefined, P<0.001) and to have touched him (83% vs. 0%, OR undefined, P<0.001). Although the source of infection for the index case was not identified, 50% of Pteropus bats sampled from near the outbreak area 1 month after the outbreak had antibodies to NiV confirming the presence of the virus in the area. The outbreak was spread by person-to-person transmission. Risk of NiV infection in family caregivers highlights the need for infection control practices to limit transmission of potentially infectious body secretions.

Key words: Bangladesh, Nipah virus, person-to-person transmission.

INTRODUCTION Antibodies reactive to NiV antigen have been de- tected in pteropid bats in both India and Bangladesh In Bangladesh, Nipah virus (NiV) was first identified [1, 5]. as the cause of an outbreak of encephalitis in 2001 Person-to-person transmission of NiV infection, in Meherpur District [1, 2]. Four additional out- following human infection directly from the environ- breaks were identified between 2001 and 2005 [1–4]. ment, was noted in previous outbreaks in the Indian subcontinent. In a NiV outbreak in Siliguri, India

* Author for correspondence: Dr N. Homaira, Programme on in 2001, 45 patients (75%) had a history of hospital Infectious Disease and Vaccine Sciences, Health System and exposure to other patients with NiV infection [6]. Infectious Disease Division, ICDDR,B, 68, Shahid Tajuddin In , Bangladesh in 2004 NiV case- Ahmed Sharani, Mohakhali, Dhaka-1212, Bangladesh. (Email: [email protected]) patients in Faridpur were seven times more likely than 2 N. Homaira and others non-patients to have had close contact with one of the immunosorbent assay (ELISA) that detects IgM NiV patients [odds ratio (OR) 6.7, 95% confidence antibodies specific for NiV antigens [7]. interval (CI) 2.9–16.8, P<0.001] [2]. We defined a confirmed case of NiV infection as a On 9 February 2007, a physician at Rangpur Medi- suspected case-patient with detectable IgM to NiV. cal College Hospital, one of 10 hospitals involved in The team defined a probable NiV case-patient as a active NiV encephalitis surveillance in Bangladesh, patient with fever and altered mental status who lived reported a cluster of fatal encephalitis involving a in the same village as a confirmed case-patient during husband and a wife residing in the Haripur the outbreak period, but from whom serum was not (subdistrict) of Thakurgaon District. Both patients available because the patient died before a specimen had similar symptoms and died within an interval could be collected. of 2 weeks. A collaborative team including the Insti- tute of Epidemiology Disease Control and Research Qualitative study (IEDCR) and the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), began an A team of experienced anthropologists conducted investigation on 10 February 2007. The objectives in-depth interviews and informal discussions with of the investigation were to identify the cause of the available confirmed and probable case-patients, their outbreak and the risk factors for developing illness. family members and friends, and other residents in these communities with the goals of exploring poten- tial exposures to NiV and identifying appropriate METHODS proxy respondents for deceased cases or cases that were too sick to interview. The anthropologists also Case definition and identification collected information about symptoms of the disease, We defined suspected case-patients as persons having caregiving practices and health facility utilization by fever with altered mental status or new onset of persons affected by the outbreak. seizures (severe illness), or persons having fever with headache or cough (mild illness), residing in the out- Case-control study break area with an onset of illness between 15 January and 28 February 2007. The team visited the outbreak We conducted a case-control study to investigate village and asked the community health workers and exposures associated with NiV infection, including community residents if they were aware of any patient person-to-person transmission. Probable and con- who was suffering from fever with seizure or altered firmed case-patients were enrolled as cases. We selec- mental status, or who had died from these symptoms ted three controls for each case-patient. Controls in their neighbourhood. We also asked them about were selected starting from the fourth closest house to case-patients suffering from fever with headache and/ the case-patient where no members were ill during or cough. The team then visited the local hospital the outbreak. The household resident closest in age in order to identify suspected case-patients. Team to the case-patient was eligible to participate as a members also investigated all the deaths in the out- control. Participation was voluntary. If the selected break village between January and February. We ob- household resident declined to participate, a resident tained a history of illness and general information from the next closest house was asked to participate. about exposures for each suspected case-patient. We The qualitative team selected proxy respondents asked the local health authority of the affected sub- for each case-patient who had died or was unable to district to report to the IEDCR if they identified respond. The proxy respondents included family any further suspected case-patient having fever and members and friends of the case-patients who were altered mental status or seizures who sought treat- most knowledgeable about their activities and prob- ment in the local subdistrict health complex during able risk exposures in the preceding 1 month before February. illness. Multiple proxy respondents were common. The team collected blood samples from living sus- The investigation team used a standardized question- pected case-patients, which were centrifuged in the naire to collect information on demographics, symp- field and transported on wet ice to IEDCR, where toms of illness, and possible risk factors associated they were stored at x70x. Samples were tested with with NiV transmission including history of con- an immunoglobulin M (IgM) capture enzyme-linked sumption of date palm juice prior to illness, exposure Person-to-person transmission of NiV 3 to animals and exposure to ill patients, including outbreak investigation. Bat capture and sample col- touching, staying in the same room, feeding, sharing a lection was conducted under a protocol approved by bed or cleaning body secretions of a NiV patient. the Institutional Animal Care and Use Committee.

Bat survey RESULTS A team of veterinarians from ICDDR,B with assist- Descriptive epidemiology ance from the Consortium for Conservation Medicine located two bat roosts which were 1 km and 15 km Eleven serum samples were collected from 13 sus- distant from the outbreak village. Bats were captured pected case-patients. Five suspected case-patients using mist nets and were anaesthetized during sample had IgM antibodies against NiV by capture ELISA collection and released at the point of capture after and were thus confirmed cases. Two suspected case- sampling from 24 February to 9 March 2007. All patients had fever and altered mental status, but died the captured bats from which blood samples were before samples could be collected and were categor- collected were P. giganteus. ized as probable cases. These two probable cases were All bat blood samples were kept on ice until the the index case and his wife. The remainder of the end of each day when serum was separated and stored analysis was performed on these seven confirmed or in liquid nitrogen. At the end of each day, blood probable case-patients. Five of these case-patients samples were transferred to liquid nitrogen and (three confirmed and two probable) had fever with transported to ICDDR,B where they were stored at altered mental status and three (60%) of them died. x70 xC and then shipped on dry ice to the Australian A total of five case-patients, including the two prob- Animal Health Laboratory for laboratory diagnosis. able cases, were hospitalized. The mean age of case- All the blood samples were assayed for antibodies patients was 24 years (range 19–30 years) and five against NiV using a serum neutralization test. (71%) were male. The median duration from onset of fever to death was 5.6 days (range 5–7) (Table 1). Fever (100%), altered consciousness (71%) along Statistics with vomiting (71%) and cough (71%) were the most We analysed socio-demographic and clinical profiles common symptoms (Table 1). of the case-patients using descriptive statistics. For the case-control study, we used ORs to estimate the Qualitative findings association of each exposure with disease and calcu- lated 95% CIs around the ORs. We used the x2 test The index case first developed fever on 21 January when expected cell sizes were >5 and Fisher’s exact 2007 which progressed to headache, cough, breathing test when expected cell sizes were <5 and considered difficulties, convulsions, loss of consciousness and association to be statistically significant if the P value finally death 5 days later. In total 14 people who were was <0.05. We used an unmatched analysis because family members, relatives or friends had physical neighbours were chosen as controls to ensure that contact with the index case when he was ill; six (43%) controls and case-patients were representative of the of them developed NiV infection. Five of the sub- same population and not to control for confounding sequent cases had contact with the index case only factors. Because the primary hypothesis was that the during the last 2 days of his illness ( index case was the source of NiV transmission for 7–14 days). The dates of illness onset for subsequent the subsequent cases, we excluded the index case, but cases ranged from 2 to 8 February 2007 (Fig. 1). None none of the controls in the analyses of person-to- of the caregivers of the subsequent cases developed person transmission. illness. During the first 4 days of illness the index case was cared for at home, primarily by his wife and sister- Ethics in-law. They fed him, cleaned him and wiped froth All human study participants gave informed consent and saliva from his mouth. They also massaged oil on for participation in this investigation. The Ethical his head and body to relieve him of pain. His wife Review Committee at ICDDR,B reviewed and ap- shared the same bed with him and provided care proved a protocol for encephalitis surveillance and throughout his illness. She became severely ill 14 days 4 N. Homaira and others

3

2

1 Number of cases

0 151617181920212223242526272829303112345678910 January February Fig. 1. Distribution of NiV cases by date of onset of illness, Haripur Upazila (subdistrict), Thakurgaon District, Bangladesh, January–February 2007. %, Alive; &, died.

Table 1. Characteristics of case-patients, Haripur Upazila, Thakurgaon District, Bangladesh, February 2007

Characteristics n=7 (%) Age Mean (years) 24 Median (range) 24 (19–30) Male 5 (71) Occupation Student 2 (29) Housewife 1 (14) Businessman 2 (29) Driver 2 (29) Clinical feature Fever 7 (100) Severe fatigue/weakness 6 (86) Headache 3 (43) Vomiting 5 (71) Cough 5 (71) Fig. 2. Chest X-ray of the index case showing features of Respiratory distress 4 (57) acute respiratory distress syndrome. Altered mental status 5 (71) Muscle pain 4 (57) Restlessness 4 (57) during this period showed diffuse bilateral opacity in Unconscious 2 (29) both lung fields suggesting features of acute respirat- Joint pain 1 (14) ory distress syndrome (Fig. 2). The friend became ill Case fatality 3 (43) 11 days later and died after 7 days. The cousin also Onset of illness to death (n=3), 5.6 (5–7) mean (range) became ill 14 days after his physical contact with the index case. The day after his chest radiograph, the index case developed reduced level of consciousness, and was after the husband’s illness began and died within admitted to a hospital where he died on the same day. 6 days of illness. The driver of a micro bus who helped transport and A day before his death, the index case developed a carry him to the hospital developed NiV infection severe cough and breathing difficulty. He was taken 10 days after exposure. to a local doctor accompanied by a friend and a While the index case was hospitalized, his wife’s cousin. A chest radiograph of the index case taken sister and one of his friends visited him in the hospital Person-to-person transmission of NiV 5

Table 2. Bivariate analysis of risk factors for , Haripur Upazila, Thakurgaon District, Bangladesh, February 2007

No. (%) of No. (%) of cases with controls with Risk factors this risk factor this risk factor OR 95% CI P value

Male sex 4 (67%) 8 (38%) 3.25 0.48–22 0.2 Climbed trees 1 (17) 4 (19%) 0.85 0.07–9.41.00 Physical contact with living animal Pig 0 (0%) 0 (%) Undefined Fruit bat 0 (0%) 0 (0%) Undefined Cow 4 (67%) 13 (62%) 1.23 0.182–8.33 1.00 Goat 2 (33%) 9 (43%) 0.67 0.099–4.51.00 Ate any animal that had been sick 0 (0%) 1 (5%) Undefined 1.00 Drank raw date palm sap 1 (17%) 0 (0%) Undefined 0.22 Visited the index case in a hospital 6 (100%) 0 (0%) Undefined <0.001 Touched the index case when he was sick 5 (83.3%) 0 (0%) Undefined <0.001 Been present in the same room with the index 6 (100%) 2 (9.5%) Undefined <0.001 case when he was sick Been present in the same room with the index 6 (100%) 0 (0%) Undefined 0.04 case when he was coughing

OR, Odds ratio; CI, confidence interval. and fed and touched him. Both of them developed OR undefined, P=0.000) the index case. In a sub- NiV infection within 10 days of contact. analysis in those who stayed in the same room with the index case, case-patients were more likely than controls to be present in the same room when he was Case-control study coughing (100% vs. 0%, OR undefined, P=0.04). We used proxy interviews for the three dead case- Only case-patients had hospital exposure to other patients, but not for any controls. The mean age NiV case-patients (86% vs.0%,P=0.000), with for cases and controls was similar [mean age (¡S.D.) all reporting visits to the index case in the hospital 24¡4 years in cases vs.24¡7 years in controls, (Table 2). t=x0.097, P=0.9]. Cases were more likely to be males than controls but this could be due to chance Bat study (67% males in case-patient group vs. 38% in control group, OR 3.2, 95% CI 0.5–22, P=0.2). The team captured and sampled 118 P. giganteus NiV case-patients were more likely than controls bats; 29 of which were juvenile bats. Of the 67 bats to have consumed raw date palm sap in the 15 days sampled 1 km from the outbreak village, 34 (51%) prior to illness (29% in case-patients vs. 0% in con- tested positive on serum neutralization test [median trols, OR undefined, P=0.056). Two (29%) of the titre 30, range 5 to >640]. Three of the 34 serum case-patients including the index case who had con- neutralization test-positive bats had NiV antibody sumed raw date palm juice bought it from a vendor titres >640. In the neighbouring village, 15 km away, in the local village market. Although there were 27/51 bats (53%) had serum neutralizing antibodies sick goats in the outbreak-affected community, none to NiV [median titre 20, range 5–320]. Of the 61 of the cases or controls had any contact with them or pteropid bats that were seropositive seven were any other sick animal within 15 days prior to illness. juvenile bats [median titre 15, range 5–20]. Moreover, there was no report of contact with fruit bats. DISCUSSION In the analysis for person-to-person transmission, case-patients were more likely than controls to have Several lines of evidence suggest person-to-person been present in the same room with (100% vs.9.5%, transmission as the primary route of transmission in OR undefined, P=0.000) or touched (83% vs.0%, this outbreak. The curve showing a gap of 6 N. Homaira and others

12–18 days between the single primary case and the from several proxy respondents thus reducing the secondary cases corresponds with the incubation likelihood that we failed to collect information on period of human NiV infection [8]. Many of the index probable exposure to risk factors. Another limitation case’s contacts (43%), who came in physical contact is the lack of serological data from controls. There with the index case when he was ill, subsequently is evidence of of NiV from became ill. In the case-control study, case-patients Malaysia [16] which could have reduced power to were significantly more likely to be in contact with the identify association due to erroneous inclusion of index case and were significantly more likely to be cases as controls. Even with this potential limitation near him when he was coughing. As subsequent cases our results identified a biologically credible pathway were limited to close contacts of the primary case, and for transmission. none of the contacts of the subsequent cases devel- Findings from outbreaks in Siliguri and Faridpur oped illness, we conclude that the index case was the illustrate that human-to-human transmission has only NiV transmitter in this outbreak. occurred repeatedly in the Indian subcontinent. The Five (83%) of the subsequent cases came in contact social norm in Bangladesh is that family members with the index case only during the last 2 days of his and loved ones provide hands-on care to sick illness when he developed respiratory symptoms. NiV patients [13]. Further, hospital healthcare workers in has been isolated from human saliva, urine, nasal and Bangladesh are reluctant to provide hands-on care to pharyngeal secretions [9, 10] and there is evidence admitted patients which increases the risk of trans- of spread of NiV infection from direct contact with mission to family members and relatives who provide respiratory secretions or other body secretions of in- care without any training or supplies to reduce the fected pigs and humans [2, 11, 12]. The probability risk of transmission [13]. Efforts to educate care- of NiV transmission is probably amplified during givers of their risk especially at later stages of illness, the last stages of illness when respiratory symptoms while maintaining sensitivity to cultural mores, and become more prominent and perhaps the concen- promoting basic infection control practices such as tration of virus in respiratory secretions increases. In washing hands with soap after handling patients and Bangladesh, as the level of physical contact with the avoiding close physical contact [2] could limit trans- patient intensifies with the severity of the disease [13], mission of NiV and other in people who care this further increases the risk of transmission. for sick patients. The NiV neutralizing antibody was >50% in the bats sampled from the outbreak area ACKNOWLEDGEMENTS which suggests that NiV has circulated in this popu- lation of bats. The result is consistent with findings The authors thank all the study participants for their in other pteropid bat populations in Malaysia, India, contribution at a very difficult time. We gratefully and Bangladesh [1, 5, 14, 15]. The bat survey was acknowledge the relentless effort of the field officers performed approximately 1 month after the onset of involved in data collection and compilation and co- illness in the index case, and it is possible that infected operation of the staff at Rangpur Medical College bats were present in the colony around the time of the Hospital and Sadar Hospital. Our gratitude first human infection. Furthermore, the index case to the Civil Surgeon of Thakurgaon District and had no evidence of exposure to clinically ill domestic the Upazila Health and Family Planning Officer of animals. He also had history of drinking raw date Haripur subdistrict for their extensive cooperation palm juice before his illness which has been associated with the investigation. We are also grateful to the with NiV infection in a previous outbreak inves- Australian Animal Health Laboratory for their sup- tigation [3]. These lines of evidence suggest that the port with the animal investigation. virus was probably transmitted directly from its This work was funded by the Centers for Disease , rather than an intermediate dom- Control and Prevention (CDC), Atlanta, the U.S. estic animal. National Institutes of Health, International Collab- A limitation of our study is its reliance on proxy orations in Infectious Disease Research (ICIDR) interviews for some of the case-patients. This may Opportunity Pool, the Government of Bangladesh have obscured some exposure information. However, (GoB) through IHP-HNPRP, an NIH/NSF ‘Ecology we started our investigation within 14 days of the of Infectious Diseases’ award from the John E. death of the index case, and collected information Fogarty International Center 2R01-TW005869, Person-to-person transmission of NiV 7

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